Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
J Org Chem. 2010 Nov 19;75(22):7505-13. doi: 10.1021/jo1010203. Epub 2010 Jul 29.
Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, both inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12-C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).
详细介绍了磷丝菌素(2)的全合成、相对和绝对立体化学的分配,以及先前作为亚磷丝菌素(1)的天然产物的结构重新分配,即磷酸酯与硫酸盐单酯的关系。使用真实材料的研究证实,磷丝菌素而不是亚磷丝菌素是蛋白磷酸酶 2A(PP2A)的有效和选择性抑制剂,这确定了其抗肿瘤活性的作用机制。还披露了对一系列关键合成类似物的合成和评估的研究扩展,这突出了天然产物磷酸单酯(与硫酸盐或游离醇相比,均无活性且相差 250 倍)、α,β-不饱和内酯(12 倍)和疏水 Z,Z,E-三烯尾部(C12-C22,约 200 倍)的重要性,包括其不饱和性的独特重要性(相差 50 倍,且不再具有 PP2A 选择性)。